**3. GSK3**

GSK3 is a Ser/Thr kinase of the CMGC family of proline-directed kinases that is highly conserved in all eukaryotes. In mammals, it is ubiquitously expressed in all tissues and subcellular organelles, most highly in the brain [11]. There are 2 isoforms encoded by separate genes (chromosome 19q13.2 for GSK3α and chromosome 3q13.3 for GSK3β) [11]. Their kinase domains are 98% homologous and their substrate specificities are similar, but not identical [12]. A splice variant of GSK3β containing a 13 amino acid insert in the catalytic domain is specif‐ ically expressed in the brain [13], although its function is only just beginning to be investigated [12]. Interestingly, GSK3 is one of the most unusual kinases in the human genome for 3 main reasons; 1) Most (if not all) substrates require 'priming' phosphorylation 4 or 5 residues Cterminal to the GSK3 target site by another kinase *before* they can be efficiently phosphorylated by GSK3 [14]. 2) GSK3 is highly active in cells under basal conditions, opposite to most other kinases. 3) Phosphorylation of GSK3 at an N-terminal serine residue *inhibits* its kinase activity (Ser21 in GSK3α, Ser9 in GSK3β) [15, 16]. This phosphoserine acts as a pseudo-substrate and binds to the phosphate-binding pocket on GSK3, preventing interaction with primed sub‐ strates [17]. Phosphorylation is mediated by members of the AGC family of kinases (e.g. Akt) and commonly occurs downstream of growth factor and PI3K signaling [15]. Activation of the canonical Wnt signaling pathway also inhibits GSK3 activity, preventing phosphorylation of β-catenin, although this is not mediated by N-terminal phosphorylation, but by proteinprotein interactions [18, 19]. GSK3 is also modified by phosphorylation at a tyrosine residue on the activation loop of the kinase domain (Tyr279 for GSK3α and Tyr216 for GSK3β). Phosphorylation at these sites is absolutely required for kinase activity and is most likely constitutively modified (i.e. not regulatable) [20, 21].
