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

By Catharina Medrek, Göran Landberg, Tommy Andersson and Karin Leandersson


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 β-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 Ca2+-dependent cell-cell adhesion. Furthermore, Wnt-5a/casein kinase Iα (CKIα)-specific Ser-45 phosphorylation of β-catenin is associated with an increased complex formation of β-catenin/E-cadherin. Mutation of Ser-45 decreases the β-catenin/E-cadherin association. Also, the inhibitory effect of Wnt-5a on breast epithelial cell invasion is reduced upon mutation of β-catenin-Ser-45. The Wnt-5a-CKIα-induced Ser-45 phosphorylation does not lead to degradation of β-catenin. Finally we show that human breast cancers lacking Wnt-5a protein have a significantly lower level of membrane-associated β-catenin. Down-regulation of Wnt-5a expression and subsequent reduction of membrane-associated β-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

Topics: Mechanisms of Signal Transduction
Publisher: American Society for Biochemistry and Molecular Biology
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Provided by: PubMed Central
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