Wnt-5a-CKI{alpha} signaling promotes {beta}-catenin/E-cadherin complex formation and intercellular adhesion in human breast epithelial cells.
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 beta-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 Ialpha (CKIalpha)-specific Ser-45 phosphorylation of beta-catenin is associated with an increased complex formation of beta-catenin/E-cadherin. Mutation of Ser-45 decreases the beta-catenin/E-cadherin association. Also, the inhibitory effect of Wnt-5a on breast epithelial cell invasion is reduced upon mutation of beta-catenin-Ser-45. The Wnt-5a-CKIalpha-induced Ser-45 phosphorylation does not lead to degradation of beta-catenin. Finally we show that human breast cancers lacking Wnt-5a protein have a significantly lower level of membrane-associated beta-catenin. Down-regulation of Wnt-5a expression and subsequent reduction of membrane-associated beta-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.
Medrek
Catharina
C
Cell and Experimental Pathology and Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Universitetssjukhuset-Malmö Allmänna Sjukhus, 20502 Malmö, Sweden.
Landberg
Göran
G
Andersson
Tommy
T
Leandersson
Karin
K
D001940:Breast / Q000166:cytology* / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D048128:Casein Kinase Ialpha / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin; D012694:Serine; D048128:Casein Kinase Ialpha