In the early 1980's I found that glycogen synthase was phosphorylated con-stitutively by a protein kinase that I initially termed GSK-5, but which is nowdays called CK2. However, in contrast to GSK-3, the phosphorylation of glycogen synthase by CK2 did not decrease its activity . Colin Picton, a postdoc in the lab, then made the surprising finding that, although phosphory-lation by CK2 did not alter the activity of glycogen synthase directly, it was a prerequisite for the GSK-3-catalysed phosphorylation and inactivation of glycogen synthase . Colin also identified the serine residue phosphory-lated by CK2 and showed that it was located just C-terminal to the serine residues phosphorylated by GSK-3 . The function of CK2-catalysed phosphorylation was therefore to "prime" glycogen synthase for phosphorylation by GSK-3. Brian Hemmings in the lab then found that phosphorylation by CK2 also "primed" the Type-2 regulatory subunit of cyclic AMP-dependent protein kinase for phosphorylation by GSK-3 , demonstrating that the requirement for a "priming phosphorylation" is not unique to glycogen synthase. These observations were extended by Peter Roach in elegant experiments which demonstrated that the optimal recognition sequence for GSK-3 is Ser/Thr-Xaa-Xaa-Xaa-pSer/pThr (where pSer and pThr are phosphoserine and phosphothreonine, respectively, and Xaa is any amino acid) . We now know that the prior action of a "priming" kinase is critical for the GSK-3 -catalysed phosphorylation of many proteins and that the identity of the "priming"kinase varies from substrate to substrate.
Much later, the specific binding site for the priming phosphate of the substrate was identified, and the PKB-catalysed phosphorylation of GSK-3 was shown to transform its N-terminus into a pseudosubstrate which inhibits GSK-3 by interacting with the binding site for the priming phosphate [29,30]. It is therefore important to emphasise that the extent to which phosphoryla-tion of GSK-3 inhibits activity is likely to vary from substrate to substrate and will clearly depend on the strength of interaction between GSK-3 and its different substrates. Phosphorylation may therefore only inhibit the phosphory-lation of a subset of the substrates of GSK-3 under physiological conditions, a critical point that is frequently overlooked.
GSK-3: THE PRESENT AND THE FUTURE
Although GSK-3 was originally identified as a protein kinase involved in the regulation of glycogen metabolism, we now know that it participates in the control of many cellular processes, including embryonic development, where it is a key component of the Wnt signalling pathway, as well as gene transcription and neuronal cell function, which will be apparent from reading the chapters in this book. Undoubtedly, many more substrates for GSK-3 remain to be discovered in these and other processes. Another extremely exciting development in recent years has been has the advent of potent and specific inhibitors of GSK-3, which have not only become powerful pharmacological reagents with which to study its functions, but also have therapeutical potential for the treatment of diabetes, stroke, Alzheimer's and other diseases. These aspects are the major topic of Sections B and C of this book. However, these compounds are still at the preclinical stage and whether inhibitors of GSK-3 can be used safely for prolonged periods remains to be seen.
While I was writing this foreword I noticed that well over 1000 papers were published over the two year period from January 1st 2004 to December 31st 2005, many more than in the previous two years. Thus research on GSK-3 is clearly continuing at an ever increasing pace and the study of this enzyme is clearly going to continue to be a vibrant and active field of research for many years to come.
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