Phospho-regulation of β-Catenin Adhesion and Signaling Functions

Daugherty, Rebecca L.; Gottardi, Cara J.

doi:10.1152/physiol.00020.2007

Cited by 222 publications

(266 citation statements)

References 86 publications

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“…In the absence of either Wnt or PI3K signalling, b-catenin is part of a complex including axin, adenomatous polyposis coli and glycogen synthase kinase-3b (GSK-3b). The latter phosphorylates b-catenin at its N terminus, targeting it for proteasomal degradation (Daugherty & Gottardi, 2007). GSK-3b can be either inactivated via the Wnt pathway (Moon et al, 2004) or, of particular relevance to HCV and NS5A, subject to inhibitory phosphorylation by the PI3K effector, Akt.…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus NS5A protein interacts with -catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion

Milward

Mankouri

Harris

2009

Journal of General Virology

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Hepatitis C virus (HCV) infection is increasingly associated with the development of hepatocellular carcinoma (HCC). HCV is not thought to be directly oncogenic but, by modulating a range of cellular functions, may predispose patients to the development of liver tumours. However, the molecular mechanisms by which HCV infection might contribute to HCC remain to be characterized. In this regard, we showed previously that the HCV NS5A protein bound to the p85 regulatory subunit of phosphoinositide-3 kinase (PI3K), thereby stimulating the activity of the p110 catalytic subunit of the enzyme. One of the downstream consequences of this was the stabilization of the proto-oncogene, b-catenin, with a concomitant stimulation of its transcriptional activity. Here, we further analyse the mechanism by which NS5A mediates activation of b-catenin. Although our previous data were consistent with a role for the PI3K downstream effector kinases, Akt and glycogen synthase kinase-3b, in NS5A-mediated activation of b-catenin, we demonstrate here that it is in fact independent of both of these kinases. Truncation analysis revealed that both the N and C termini of NS5A are required for full activation of b-catenin. Furthermore, we demonstrate that NS5A, either alone or in complex with p85, is able to bind directly to b-catenin; again both N and C termini contribute to this interaction. We propose that NS5A activates bcatenin via a novel mechanism that involves a direct interaction between the two proteins and is augmented by PI3K activity. This may contribute to the association between chronic HCV infection and the development of HCC.

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Section: Introductionmentioning

confidence: 99%

Hepatitis C virus NS5A protein interacts with -catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion

Milward

Mankouri

Harris

2009

Journal of General Virology

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“…␤-Catenin is found predominantly in association with the E-cadherin cytoplasmic domain at cell-cell junctions (12). In the absence of cell-cell contact and Wnt signaling, cytosolic ␤-catenin forms a complex with adenomatous poliosis coli, Axin/conductin, casein kinases 1␣ and 1⑀, and glycogen synthase kinase-3␤ (GSK-3␤).…”

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confidence: 99%

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Burkhalter

Symowicz

Hudson

et al. 2011

Journal of Biological Chemistry

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Reversible modulation of integrin-regulated cell-matrix adhesion and epithelial (E)-cadherin-mediated cell-cell adhesion plays a critical role in the establishment of ovarian cancer metastases. In contrast to most epithelial cell-derived tumors that down-regulate E-cadherin expression during progression, acquisition of E-cadherin expression accompanies malignant transformation of the ovarian surface epithelium and is maintained in peritoneal metastases. Metastatic epithelial ovarian cancer cells are disseminated intraperitoneally and preferentially adhere via integrins to interstitial collagens in the peritoneal cavity. This study was undertaken to determine whether integrin engagement influences E-cadherin and ␤-catenin localization and function. The data demonstrate that multivalent integrin engagement results in increased internalization of E-cadherin, inhibition of GSK-3␤, elevated levels of nuclear ␤-catenin, increased ␤-catenin-regulated promoter activation, and transcriptional activation of Wnt/␤-catenin target genes. Blocking ␤-catenin transcriptional control with inhibitor of ␤-catenin and Tcf-4 reduces cellular invasion, suggesting a key role for ␤-catenin nuclear signaling in EOC invasion and metastasis. These studies support a model wherein cell-matrix engagement regulates the functional integrity of cell-cell contacts, leading to increased ␤-catenin nuclear signaling and enhanced cellular invasive activity. Furthermore, these results provide a mechanism for activation of Wnt/␤-catenin signaling in the absence of activating mutations in this pathway.Epithelial (E) 3 -cadherin is a single-span transmembrane glycoprotein that mediates calcium-dependent cell-cell adhesion via interaction with the extracellular domains of cadherins on the surface of neighboring cells (1, 2). Key functions of E-cadherin include the regulation of cell polarity and the maintenance of epithelial organization (3). Although most normal epithelia express high levels of E-cadherin, this cadherin is absent in the mesenchymally derived normal ovarian surface epithelium, which expresses neural (N)-cadherin. In most carcinomas, E-cadherin expression is down-regulated or lost, facilitating cellular dispersal, invasion, and metastasis (4). However, a unique feature of EOC is that E-cadherin becomes more abundant in primary differentiated carcinomas, with all histotypes displaying strong immunoreactivity (reviewed in Refs. 5, 6). There is less clarity regarding relative E-cadherin levels during ovarian tumor progression and metastasis. Although complete loss of E-cadherin is uncommon, reduced staining is often detected in late stage tumors and in ascites-derived tumor cells (7-9), and negative E-cadherin is predictive of poor overall survival (10, 11).␤-Catenin is found predominantly in association with the E-cadherin cytoplasmic domain at cell-cell junctions (12). In the absence of cell-cell contact and Wnt signaling, cytosolic ␤-catenin forms a complex with adenomatous poliosis coli, Axin/conductin, casein kinases 1␣ and 1⑀, and glyc...

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“…8). There are therefore three different pools of ␤-catenin; a membrane bound, a cytoplasmic that is constantly being phosphorylated and targeted for ubiquitination and degradation, and a nuclear unphosphorylated form.…”

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confidence: 99%

“…However, the mechanisms that target ␤-catenin to adhesive complexes have not yet been described. It is known that the association between ␤-catenin/E-cadherin is increased when E-cadherin is phosphorylated on serine residues 834, 836, and 842 (8). GSK-3␤ 2 and CK2 have been implicated as potential kinases.…”

mentioning

confidence: 99%

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Wnt-5a-CKIα Signaling Promotes β-Catenin/E-Cadherin Complex Formation and Intercellular Adhesion in Human Breast Epithelial Cells

Medrek

Landberg

Andersson

et al. 2009

Journal of Biological Chemistry

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Wnt-5a is a non-transforming Wnt protein that is implicated in cell polarity, adhesion, and motility. We have previously shown that low expression of Wnt-5a is a predictor of shorter disease-free survival in human breast cancer. Here, we investigated whether ␤-catenin/E-cadherin-mediated cell-cell adhesion was affected by loss of Wnt-5a in breast carcinomas, thereby promoting a metastatic behavior of the tumor. We show that Wnt-5a stimulation of human breast epithelial cells leads to an increased Ca 2؉ -dependent cell-cell adhesion. Furthermore, Wnt-5a/casein kinase I␣ (CKI␣)-specific Ser-45 phosphorylation of ␤-catenin is associated with an increased complex formation of ␤-catenin/E-cadherin. Mutation of Ser-45 decreases the ␤-catenin/E-cadherin association. Also, the inhibitory effect of Wnt-5a on breast epithelial cell invasion is reduced upon mutation of ␤-catenin-Ser-45. The Wnt-5a-CKI␣-induced Ser-45 phosphorylation does not lead to degradation of ␤-catenin. Finally we show that human breast cancers lacking Wnt-5a protein have a significantly lower level of membrane-associated ␤-catenin. Down-regulation of Wnt-5a expression and subsequent reduction of membrane-associated ␤-catenin in invasive breast cancer, can therefore contribute to a decreased cell-cell adhesion and increased motility resulting in a higher probability for metastatic disease.In a normal mammary gland the ducts are lined with epithelial cells that are both interconnected and connected to the basement membrane. Mutations in genes encoding adhesion molecules have been implicated in the progression of breast cancer (1). E-cadherin is a transmembrane, calcium (Ca 2ϩ )-dependent adhesion molecule that connects adjacent epithelial cells. The loss of cell-cell adhesion at the original tumor site has been suggested to be related to the loss of E-cadherin expression or function in many epithelial cancers (2). The E-cadherins are dynamically linked to the cytoskeleton via ␤-catenin, plakoglobin, p120, and ␣-catenin (3, 4). Mutations in the E-cadherin gene are frequent in invasive lobular breast cancers, whereas they are absent or might occur at a low frequency in the more common invasive ductal breast carcinomas (5). Despite this, a low membrane expression of ␤-catenin was recently shown to be associated with a poor outcome in human breast cancer patients (6). The question as to whether Wnt ␤-catenin signaling can affect E-cadherin-dependent cellular adhesion, or vice versa, has long been debated (7).␤-Catenin plays a role both in the ␤-catenin/E-cadherin complex and as a transcriptional regulator in the nucleus upon canonical Wnt signaling (reviewed in Ref. 8). There are therefore three different pools of ␤-catenin; a membrane bound, a cytoplasmic that is constantly being phosphorylated and targeted for ubiquitination and degradation, and a nuclear unphosphorylated form. It has previously been suggested that ␤-catenin targeted to adhesive or transcriptional complexes have distinct molecular forms that would allow it to coordinate the two processes...

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Phospho-regulation of β-Catenin Adhesion and Signaling Functions

Cited by 222 publications

References 86 publications

Hepatitis C virus NS5A protein interacts with -catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion

Hepatitis C virus NS5A protein interacts with -catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Wnt-5a-CKIα Signaling Promotes β-Catenin/E-Cadherin Complex Formation and Intercellular Adhesion in Human Breast Epithelial Cells

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