Signaling through beta-catenin and Lef/Tcf.
Beta-catenin plays a structural role in cell adhesion by binding to cadherins at the intracellular surface of the plasma membrane and a signaling role in the cytoplasm as the penultimate downstream mediator of the wnt signaling pathway. The ultimate mediator of this pathway is a nuclear complex of beta-catenin acting as a coactivtor with lymphoid enhancer factor/T cell factor (Lef/Tcf) transcription factors to stimulate transcription of a variety of target genes. Signaling through beta-catenin is regulated by modulating its degradation and nuclear translocation. In the absence of an activating signal, phosphorylation of beta-catenin by glycogen synthase kinase 3 (GSK3) acting in conjunction with adenomatous polyposis coli and axin/conductin causes beta-catenin to interact with the beta-transducin repeat-containing protein which results in its ubiquitination and degradation. Signaling from the wnt pathway activates dishevelled which, in an as yet undefined manner, inhibits the activity of GSK3 resulting in an increase in the cytoplasmic free pool of beta-catenin, and translocation into the nucleus. The integrin-linked kinase (ILK) pathway also activates beta-catenin-Lef/Tcf signaling. ILK phosphorylates GSK3 to inhibit its activity and translocates beta-catenin into the nucleus. In addition, ILK downregulates the expression of E-cadherin and upregulates Lef-1 expression. In the final step of the beta-catenin-Lef/Tcf signaling pathway, nuclear beta-catenin binds pontin52-TATA binding protein and displaces Groucho-related gene or CREB-binding protein corepressors from Lef/Tcf resulting in stimulation of transcription. During development, beta-catenin-Lef/Tcf signaling is involved in the formation of dorsal mesoderm and dorsal axis. Furthermore, defects in the beta-catenin-Lef/Tcf pathway are involved in the development of several types of cancers.
Novak
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Cancer Research, S-218, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.
Dedhar
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S
D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D060466:Axin Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D051157:Frizzled Receptors; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D019476:Insect Proteins / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010750:Phosphoproteins / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D012097:Repressor Proteins; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D051157:Frizzled Receptors; D019476:Insect Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C000606588:dsh protein, Drosophila; C110233:slmb protein, Drosophila; D044767:Ubiquitin-Protein Ligases; D038341:Glycogen Synthase Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D010749:Phosphoprotein Phosphatases