Signaling through beta-catenin and Lef/Tcf

beta-Catenin plays a structural role in cell adhesion by binding to cadheri ns at the intracellular surface of the plasma membrane and a signaling role in the cytoplasm as the penultimate downstream mediator of the wnt signali ng pathway. The ultimate mediator of this pathway is a nuclear complex of b eta-catenin acting-as a coactivator with lymphoid enhancer factor/T cell fa ctor (Lef/Tcf) transcription factors to stimulate transcription of a variet y of target genes. Signaling through beta-catenin is regulated by modulatin g its degradation and nuclear translocation. In the absence of an,activatin g signal, phosphorylation of beta-catenin by glycogen synthase kinase 3 (GS K3) acting in conjunction with adenomatous polyposis coli and axin/conducti n causes beta-catenin to interact with the P-transducin repeat-containing p rotein 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-cate nin into the nucleus. In addition, ILK downregulates the expression of E-ca dherin and upregulates Lef-1 expression. In the final step of the beta-cate nin-Lef/Tcf signaling pathway, nuclear beta-catenin binds pontin52-TATA bin ding protein and displaces Groucho-related gene or CREB-binding protein cor epressors from Lef/Tcf resulting:in stimulation of transcription. During de velopment, beta-catenin-Lef/Tcf signaling is involved in the formation of d orsal mesoderm and dorsal axis. Furthermore,: defects in the beta-catenin-L ef/Tcf pathway are:involved in the development of several types of cancers.