Multifunctional proteins with conserved structure
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.
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