Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin.
Loss of E-cadherin expression or function in tumors leads to a more invasive phenotype. In this study, we investigated whether the invasion suppressor activity of E-cadherin is mediated directly by tighter physical cell adhesion, indirectly by sequestering beta-catenin and thus antagonizing beta-catenin/T cell factor (TCF) signaling, or by other signaling pathways. To distinguish mechanisms, we expressed wild-type E-cadherin and various E-cadherin mutants in invasive E-cadherin-negative human breast (MDA-MB-231) and prostate (TSU-Pr1) epithelial carcinoma cell lines using a tetracycline-inducible system. Our data confirm that E-cadherin inhibits human mammary and prostate tumor cell invasion. We find that adhesion is neither necessary nor sufficient for suppressing cancer invasion. Rather, the invasion suppressor signal is mediated through the beta-catenin-binding domain of the E-cadherin cytoplasmic tail but not through the p120ctn-binding domain. beta-catenin depletion also results in invasion suppression. However, alteration in the beta-catenin/TCF transcriptional regulation of target genes is not required for the invasion suppressor activity of E-cadherin, suggesting the involvement of other beta-catenin-binding proteins.
Wong
Alice S T
AS
Dept. of Cell Biology, School of Medicine, University of Virginia, PO Box 800732, Charlottesville, VA 22903, USA.
Gumbiner
Barry M
BM
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D008297:Male; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009369:Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin