Inhibition of beta-catenin-mediated transactivation by cadherin derivatives.
We studied the effect of N-cadherin, and its free or membrane-anchored cytoplasmic domain, on the level and localization of beta-catenin and on its ability to induce lymphocyte enhancer-binding factor 1 (LEF-1)-responsive transactivation. These cadherin derivatives formed complexes with beta-catenin and protected it from degradation. N-cadherin directed beta-catenin into adherens junctions, and the chimeric protein induced diffuse distribution of beta-catenin along the membrane whereas the cytoplasmic domain of N-cadherin colocalized with beta-catenin in the nucleus. Cotransfection of beta-catenin and LEF-1 into Chinese hamster ovary cells induced transactivation of a LEF-1 reporter, which was blocked by the N-cadherin-derived molecules. Expression of N-cadherin and an interleukin 2 receptor/cadherin chimera in SW480 cells relocated beta-catenin from the nucleus to the plasma membrane and reduced transactivation. The cytoplasmic tails of N- or E-cadherin colocalized with beta-catenin in the nucleus, and suppressed the constitutive LEF-1-mediated transactivation, by blocking beta-catenin-LEF-1 interaction. Moreover, the 72 C-terminal amino acids of N-cadherin stabilized beta-catenin and reduced its transactivation potential. These results indicate that beta-catenin binding to the cadherin cytoplasmic tail either in the membrane, or in the nucleus, can inhibit beta-catenin degradation and efficiently block its transactivation capacity.
Sadot
E
E
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Simcha
I
I
Shtutman
M
M
Ben-Ze'ev
A
A
Geiger
B
B
D000818:Animals; D016466:CHO Cells; D015820:Cadherins / Q000737:chemistry / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002645:Chickens; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D007700:Kinetics; D051821:Lymphoid Enhancer-Binding Factor 1; D010957:Plasmids; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D051176:beta Catenin
D015820:Cadherins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin