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The proteasomal degradation of beta-catenin mediated by the glycogen synthase kinase 3beta (GSK3beta) and destruction complex is the central step in the canonical Wnt signaling pathway. However, that there are branches of Wnt signaling pathways that do not depend on beta-catenin/Tcf-mediated transcription activation has long been understood. In this study, we hypothesized that there are many more GSK3 and destruction complex-dependent proteolytic target proteins that mediate Wnt signaling in the cell. To test this hypothesis, we have developed and carried out a screen for such candidate proteins using an in vitro expression cloning technique and biochemical reconstitution of Wnt signaling in Xenopus egg cytoplasmic extracts. Forty-two proteins have been identified as potential candidates for GSK3-regulated phosphorylation, proteasomal degradation, or both, of which 12 are strong candidates for Wnt-pathway-regulated degradation. Some of them have been reported to interact with beta-catenin and implicated in the canonical Wnt signaling pathway, and other targets identified include proteins with various cellular functions such as RNA processing, cytoskeletal dynamics, and cell metabolism. Thus, we propose that Wnt/GSK3/destruction complex signaling regulates multiple target proteins to control a broad range of cellular activities in addition to beta-catenin-mediated transcription activation.
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