A partnership with the proteasome: the destructive nature of GSK3

Glycogen Synthase Kinase-3 (GSK3) was originally reported as a key enzyme of glucose homeostasis through regulation of the rate of glycogen synthesis. It has subsequently been found to influence most cellular processes, including growth, differentiation and death, as part of its role in modulating response to hormonal, nutritional and cellular stress stimuli. More than 100 protein targets for GSK3 have been proposed although only a small fraction of these have been convincingly validated in physiological cell systems. The effects of GSK3 phosphorylation on substrates includes alteration of enzyme activity, protein localisation, protein:protein interaction and protein stability. This latter form of regulation of GSK3 substrates is the focus of this review. There is an ever-growing list of GSK3 substrates that upon phosphorylation are targeted to the beta-transducin repeat containing protein (b-TrCP), thereby allowing ubiquitination of bound protein by cullin-1 and so initiating destruction at the proteasome. We propose the existence of a GSK3-b-TrCP ‘destruction hit-list’ that allows the co-ordinated removal (or stabilisation) of a set of proteins with a common physiological purpose, through control of GSK3. We identify 29 proteins where there is relatively strong evidence for regulation by a GSK3-b-TrCP axis and note common features of regulation and pathophysiology. Furthermore, we assess the potential of pre-phosphorylation (priming) of these targets (normally a prerequisite for GSK3 recognition) to provide a second layer of regulation delineated by the priming kinase that allows GSK3 to mark them for destruction. Finally, we discuss whether this knowledge improves options for therapeutic intervention.