Multifunctional proteins with conserved structure

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Glycogen synthase kinase 3 (GSK3) was originally characterized in the animal insulin signalling pathway as a serine/threonine kinase that phosphorylates glycogen synthase, the enzyme responsible for the final step in the synthesis of glycogen [1]. GSK3 functions in many developmental processes, including cell fate specification, cytoskeleton movements and programmed cell death (reviewed in [2]), with roles in human diseases, including cancer and Alzheimer’s (reviewed in [3]). In particular, GSK3 is a central player in the animal Wnt signalling pathway, where extracellular Wnt signals lead to the inactivation of GSK3. This blocks the activity of GSK3 towards β-catenin (see Glossary), which as a result is no longer degraded by the proteasome, but can build up in the nucleus and regulate target gene expression [4]. Thus, GSK3 is crucial for developmental patterning [5], a role that appears to be conserved in Dictyostelium discoideum [6]. Mammalian GSK3 exists as two isoforms, encoded by separate genes, GSK3α and GSK3β, which have a conserved kinase domain but divergent N- and C-terminal domains, which are important for regulation of function [7].

            GSK3 substrates are diverse and most of them require phosphorylation by another kinase before being phosphorylated by GSK3. This is termed as a 'priming' phosphorylation, which positions the substrate in a suitable configuration for phosphorylation by GSK3. A phosphate-binding pocket in GSK3 interacts with the primed phosphorylation [8]. In GSK3β, the phosphate-binding pocket is defined by arginine 96, arginine 180 and lysine 205 [8] (Figure 1). GSK3 is an ancient kinase, with homologues found in all eukaryotes studied to date. Unlike in animals and Dictyostelium, land plant GSK3s are encoded by relatively large multigene families whose members share high sequence similarity. In all angiosperm GSK3s so far analysed, the phosphate-binding pocket residues are identical to those in GSK3b, suggesting that plant GSK3s can phosphorylate primed substrates [9] (Figure 1). Accordingly, a proteomic study identified ten Arabidopsis thaliana (Arabidopsis) (proteins with putative GSK3 phosphorylation sites: five of these were phosphorylated at the corresponding priming site [10].

In Arabidopsis there are ten GSK3 homologues, also termed Shaggy Kinases (AtSK or ASK) in reference to the Drosophila GSK3 homologue [11]. Nomenclature of Arabidopsis GSK3s can be confusing. A full complement of names for each Arabidopsis protein, along with names for other plant GSK3s that have been studied, is given in Table 1. In the last decade, substantial progress has been made in understanding how plant GSK3s perform their diverse functions. In the following sections we will describe currently known plant GSK3 functions, discuss the molecular mechanisms of GSK3 action in plants, and highlight possible GSK3 functions in early-evolving land plants as an exciting area for future research developments.