Glycogen synthase kinase 3 (GSK-3) is a multifunctional
serine/threonine kinase found in all eukaryotes. The
enzyme is a key regulator of numerous signalling pathways, including cellular responses to Wnt,
receptor tyrosine kinases and
G-protein-coupled receptors and is involved in a wide range of cellular processes, ranging from
glycogen metabolism to cell cycle regulation and proliferation.
GSK-3 is unusual in that it is normally active in cells and is primarily regulated through inhibition of its activity. Another peculiarity compared with other
protein kinases is its preference for primed substrates, that is, substrates previously phosphorylated by another
kinase. Several recent advances have improved our understanding of
GSK-3 regulation in multiple pathways. These include the
solution of the crystal structure of
GSK-3, which has provided insight into GSK-3's penchant for primed substrates and the regulation of
GSK-3 by
serine phosphorylation, and findings related to the involvement of
GSK-3 in the Wnt/
beta-catenin and Hedgehog pathways. Finally, since increased
GSK-3 activity may be linked to pathology in diseases such as
Alzheimer's disease and
non-insulin-dependent diabetes mellitus, several new
GSK-3 inhibitors, such as the aloisines, the paullones and the
maleimides, have been developed. Although they are just starting to be characterized in cell culture experiments, these new inhibitors hold promise as therapeutic agents.