Differential Regulation of Growth-Promoting Signalling Pathways by E-Cadherin

Georgopoulos, Nikolaos T.; Kirkwood, Lisa A.; Walker, Dawn; Southgate, Jennifer

doi:10.1371/journal.pone.0013621

Cited by 32 publications

(37 citation statements)

References 55 publications

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“…(34) In contrast, in cells expressing ECD and showing stable cell-to-cell attachment, the activity of the EGFR-ERK pathway is decreased and b-catenin-T lymphocyte-specific transcription factor (TCF) signaling is inhibited. (35) In dense culture of ECD expressing airway epithelial cells, EGFR activation promotes cell differentiation with mucin production. (36) E-cadherin regulates EGFR by promoting the formation of a complex with the extracellular domain of ECD.…”

Section: Discussionmentioning

confidence: 99%

Significance of epithelial growth factor in the epithelial–mesenchymal transition of human gallbladder cancer cells

et al. 2012

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Five gallbladder cancer (GBC) cell lines were examined for morphological changes in collagen gel culture. GBh3 and HUCCT-1 cells formed tubules in response to treatment with epithelial growth factor (EGF) and hepatocyte growth factor (HGF), and showed high levels of expression of E-cadherin (ECD), and low levels of SNAIL, vimentin, transforming growth factor (TGF)-b, and nucleostemin (NS). In contrast, the GBd15 and FU-GBC-1 cell lines treated with EGF and HGF showed a scattering phenotype, and expressed low levels of ECD and high levels of SNAIL, vimentin, TGF-b, and NS. All cell lines expressed the EGF receptor, c-Met, EGF, and TGF-a, but not HGF. Transforming growth factor-b was upregulated by EGF. Knockdown of the EGF receptor abrogated both tubule formation and scattering, whereas KD of TGF-b abrogated only scattering. Knockdown of EGF induced nuclear translocation of b-catenin and Wnt-related NS induction in the scattering cell lines, but not in the tubule-forming cell lines, whereas KD of glycogen synthase kinase-3b in the tubuleforming cell lines resulted in the nuclear translocation of b-catenin and Wnt-related NS induction in response to EGF treatment. These results suggest that EGF enhances epithelial-mesenchymal transformation and acquisition of stemness in GBC cells with a scattering phenotype through the activity of b-catenin. Repression of ECD in scattering GBC cells induced the release of b-catenin from the cell adhesion complexes along the plasma membrane and its translocation to the nucleus to activate Wnt signaling, which upregulated NS. (Cancer Sci 2012; 103: 1165-1171 B iliary tract cancer is the sixth leading cause (5.1%) of cancer death in Japan, with 17 000 BTC patients dying in 2009.(1) Biliary tract cancer shows poor prognosis in spite of aggressive treatment, and the 5-year survival is only 18%.(1) Nodal metastasis is the most significant prognostic factor for GBC. (2)(3)(4) Epithelial growth factor receptor is a key factor in epithelial malignancies, and its activity enhances tumor growth, invasion, and metastasis.(5) Biliary tract cancers express EGFR in 60.7% of cases.(6) The EGFR-overexpressing GBC cases show poorly differentiated histology and decreased survival of 1.5 years in median survival.(7) Amplification and point mutations of the EGFR gene have been reported to be 1% and 15 -26.5%, respectively, in GBC.(8-10) The HGF receptor c-Met is involved in the early carcinogenesis of BTC.(11) c-Met is expressed in 74% of invasive GBC and is associated with invasive depth.(12) Because HGF is secreted from fibroblasts, c-Met activation depends on the cancer-host interaction. (13) Transforming growth factor-b is widely expressed in advanced GBC and is associated with angiogenesis and tumor-associated macrophage infiltration as well as with stromal fibrosis. (14,15) Epidermal growth factor receptor, c-Met, and TGF-b have recently been implicated in the process of EMT. (16)(17)(18)(19) Epithelial-mesenchymal transition comprises a switch in cell differentiation from polarized epithelial ...

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Section: Discussionmentioning

confidence: 99%

Significance of epithelial growth factor in the epithelial–mesenchymal transition of human gallbladder cancer cells

et al. 2012

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“…Importantly, stimulation of PI3K/Akt is paralleled by a down-regulation of the growth-promoting MEK/ERK signaling, resulting in cell cycle arrest and differentiation. 43,44 However, the link between Ecadherin expression and PI3K activity is not always unequivocal and might be context-dependent. Indeed, E-cadherin has been shown to up-regulate PTEN expression via ␤-catenin-mediated Egr1 regulation and mediates its recruitment to cell-cell junctions, leading to suppression of PI3K/Akt signaling and growth arrest in ovarian cancer cells and mammary epithelial cells.…”

Section: E-cadherin Modulates Pi3k/akt Signalingmentioning

confidence: 99%

“…[39][40][41][42][43][44] Although the exact molecular mechanisms involved are not entirely clear, current data suggest that nascent cell-cell contact formation via E-cadherin results in the activation of the c-Src kinase, 39 leading to phosphorylation and subsequent recruitment of the PI3K p85 subunit to AJs. [40][41][42] Next, PtdIns(3,4,5)P3 production in these nascent Ecadherin contacts triggers the recruitment of proteins containing pleckstrin homology domains, including Akt.…”

Section: E-cadherin Modulates Pi3k/akt Signalingmentioning

confidence: 99%

“…Phosphatidylinositol 3-kinases (PI3K) phosphorylate protein kinase B (Akt), thereby regulating various processes. Depending on the context, the E-cadherin/catenin complex might stimulate this cascade by recruiting and activating PI3K at the E-cadherin/catenin complex, [39][40][41][42][43][44] or suppressing this cascade by recruiting PTEN to the E-cadherin/catenin complex. 45,46 PI3K/Akt signaling typically instructs antiinflammatory activation of macrophages and DCs.…”

Section: E-cadherin Modulates Rho-family Gtpase Activitymentioning

confidence: 99%

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Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

Bossche

Malissen

Mantovani

et al. 2012

Blood

140

121

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E-cadherin is best characterized as adherens junction protein, which through homotypic interactions contributes to the maintenance of the epithelial barrier function. In epithelial cells, the cytoplasmic tail of E-cadherin forms a dynamic complex with catenins and regulates several intracellular signal transduction pathways, including Wnt/␤-catenin, PI3K/Akt, Rho GTPase, and NF-B signaling. Recent progress uncovered a novel and critical role for this adhesion molecule in mononuclear phagocyte functions. Ecadherin regulates the maturation and migration of Langerhans cells, and its ligation prevents the induction of a tolerogenic state in bone marrow-derived dendritic cells (DCs). In this respect, the functionality of ␤-catenin could be instrumental in determining the balance between immunogenicity and tolerogenicity of DCs in vitro and in vivo. Fusion of alternatively activated macrophages and osteoclasts is also Ecadherin-dependent. In addition, the Ecadherin ligands CD103 and KLRG1 are expressed on DC-, T-, and NK-cell subsets and contribute to their interaction with E-cadherin-expressing DCs and macrophages. Here we discuss the regulation, function, and implications of Ecadherin expression in these central orchestrators of the immune system. (Blood. 2012;119(7):1623-1633) IntroductionCadherins are transmembrane or membrane-associated glycoproteins that mediate Ca 2ϩ -dependent cell-cell adhesion and have mainly been described for their instrumental role during morphogenesis of a variety of organs. 1 The cadherin superfamily composes classic type I cadherins, closely related type II cadherins, desmosomal cadherins, protocadherins, and several cadherin-related molecules. Cadherin-1 (encoded by Cdh1), also known as CD324, uvomorulin, or E-cadherin, in which the "E" stands for "epithelial," is the founding member of the classic type I cadherin family, which also includes N-cadherin (neural, Cdh2), P-cadherin (placental, Cdh3), Cdh4), and VE-cadherin (vascular endothelial, Cdh5). For several decades, E-cadherin has been known as a major constituent of adherens junctions (AJs), mediating strong homotypic adhesion between neighboring epithelial cells, thereby safeguarding epithelial barrier integrity. 2 The lack of functional tight junction and desmosome formation in the absence of E-cadherin emphasizes its central role in the regulation of epithelial cell-cell contacts. 3 Cell-cell adhesion is mainly executed by the formation of E-cadherin trans-homodimers. Indeed, the E-cadherin molecule contains an ectodomain composed of 5 extracellular cadherin (EC1-5) repeats (550 aa in total), in which EC1 composes the HAV peptide sequence responsible for homophilic interactions, a transmembrane region, and a cytoplasmic tail (150 aa). 2 The latter can be further subdivided into a ␤-catenin binding domain and a membrane proximal cytoplasmic/conserved domain, whose core sequence motif DEEGGGEED is important for p120-catenin binding, resulting in the stabilization of the E-cadherin/catenin complex at the cell surface. 4 E-cadhe...

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“…Recent studies implicate that cadherins regulate interaction of growth factor receptors with ligands and modulate their signaling. Cadherins bind to growth factor receptors, including transforming growth factor- receptor (TGFBR), fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR), vascular endothelial cell growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), and the cytoplasmic domain can suppress growth-promoting cell signaling, such as Src, phosphatidylinositol-3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) pathways (Reddy et al, 2005;Suyama et al, 2002;Georgopoulos et al, 2010;Cavallaro & Dejana, 2011). Sensitivity to the EGFR inhibitor, cetuximab, requires intact Ecadherin expression and silencing of E-cadherin reduces responsiveness to the inhibitor (Black et al, 2008).…”

Section: Roles Of E-cadherin In the Epitheliummentioning

confidence: 99%

Cadherin Expression and Progression of Squamous Cell Carcinomas of the Oral Cavity

Imai¹,

Maeda²,

Chiba³

2012

Squamous Cell Carcinoma

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Differential Regulation of Growth-Promoting Signalling Pathways by E-Cadherin

Cited by 32 publications

References 55 publications

Significance of epithelial growth factor in the epithelial–mesenchymal transition of human gallbladder cancer cells

Significance of epithelial growth factor in the epithelial–mesenchymal transition of human gallbladder cancer cells

Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

Cadherin Expression and Progression of Squamous Cell Carcinomas of the Oral Cavity

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