GSK3 takes centre stage more than 20 years after its discovery

Identified originally as a regulator of glycogen metabolism, glycogen synth ase kinase-3 (GSK3) is now a well-established component of the Writ signall ing pathway, which is essential for setting up the entire body pattern duri ng embryonic development. It may also play important roles in protein synth esis, cell proliferation, cell differentiation, microtubule dynamics and ce ll motility by phosphorylating initiation factors, components of the cell-d ivision cycle, transcription factors and proteins involved in microtubule f unction and cell adhesion. Generation of the mouse knockout of GSK3 beta, a s well as studies in neurons, also suggest an important role in apoptosis. The substrate specificity of GSK3 is unusual in that efficient phosphorylat ion of many of its substrates requires the presence of another phosphorylat ed residue optimally located four amino acids C-terminal to the site of GSK 3 phosphorylation. Recent experiments., including the elucidation of its th ree-dimensional structure, have enhanced our understanding of the molecular basis for the unique substrate specificity of GSK3. Insulin and growth fac tors inhibit GSK3 by triggering its phosphorylation, turning the N-terminus into a pseudosubstrate inhibitor that competes for binding with the primin g phosphate of substrates. In contrast. Wnt proteins inhibit GSK3 in a comp letely different way. by disrupting a multiprotein complex comprising GSK3 and its substrates in the Wnt signalling pathway, which do not appear to re quire a priming phosphate. These latest findings have generated an enormous amount of interest in the development of drugs that inhibit GSK3 and which may have therapeutic potential for the treatment of diabetes., stroke and Alzheimer's disease.