Identification of Wnt/GSK3 regulated proteolysis targets in addition to B-catenin

The Wnt signaling pathway regulates a variety of cellular processes including cell proliferation, differentiation and migration in embryonic development and adult tissue renewal, as well as in diseases such as cancer. In the canonical Wnt signaling pathway, glycogen synthase kinase-3 (GSK3) phosphorylation mediates proteasomal targeting and degradation of Β-catenin via the destruction complex. However, it has long been understood that there are branches of Wnt signaling pathways that do not depend on the Β-catenin/Tcf mediated transcription activation, and that GSK3 regulates protein stability in a variety of signaling pathways other than Wnt signaling. In this study, we developed and carried out a biochemical screen that discovered multiple additional protein substrates whose stability is regulated by Wnt signaling and/or GSK3 and these have important implications for Wnt/GSK3 regulation of different cellular processes (1). We also designed and executed a bio-informatics based search that identified potential GSK3 and Β-Trcp mediated proteolysis targets. Therefore, Wnt/GSK3/destruction complex signaling regulates multiple target proteins to control a broad range of cellular activities in addition to Β-catenin mediated transcription activation, and that GSK3 phosphorylation dependent proteolysis is a widespread mechanism that the cell employs to regulate a variety of cell processes in response to signals.