Initially shown to phosphorylate glycogen synthase, GSK3 is a multifunctional kinase that regulates numerous cellular processes. Unlike many kinases, it is generally active in cells and inhibited by signalling;moreover, it tends to favour substrates that have already been phosphorylated(`primed') by other kinases. In a Commentary on p. 1175, Bradley Noble and James Woodgett review recent advances in our understanding of the structure and functions of GSK3. The solving of its crystal structure, for example, has revealed where the priming phosphate group on the substrate binds and indicates that this optimizes orientation of the kinase domain and positions the substrate correctly in the catalytic groove. Other studies have shown that the major transducers in Wnt and Hedgehog signalling — β-catenin and Cubitus interruptus — are GSK3 targets and primed by casein kinase I and protein kinase A. Given the abnormal GSK3 activity associated with conditions such as Alzheimer's and diabetes,...

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