Missing links in GSK3 regulation.

The Wnt–GSK3–b-catenin pathway is central to proesses at many stages of development and is highly conerved between species (Wodarz and Nusse, 1998). It is a omplex pathway with branching outputs and alternative nputs at almost every step (Arias et al., 1999) and it herefore touches on many other regulatory systems. These eatures of Wnt–GSK–b-catenin signaling perhaps reflect ow ancient this pathway is evolutionarily (Gerhart, 1999), llowing time for the signaling apparatus to accrete addiions and variations. Its inappropriate activation is also linically important in many cancers (Polakis et al., 1999). Glycogen synthase kinase 3 (GSK3) is a central enzyme in his pathway. It was originally identified as a serine/ hreonine kinase involved in the regulation of glycogen by nsulin (Woodgett, 1990; Welsh and Proud, 1993) and is now mplicated in many different biological processes including umorigenesis, cell survival, and developmental patterning Fig. 1). Some of its roles in development were recently eviewed in this journal (Ferkey and Kimelman, 2000). SK3 is involved in a number of quite distinct signal ransduction pathways with different inputs and outputs e.g., Hunter, 1997). Thus, an intriguing and important uestion is how cross talk between these pathways is revented. Recent progress in studies of Wnt signaling has uggested some possible answers to this question. However, he mechanism by which Wnt actually regulates GSK3 is till unknown. In this regard, it is the questions that are just eginning to emerge.