Glycogen synthase kinase-3 (GSK-3)1
is a Ser/Thr kinase evolutionarily conserved from yeast to humans. In mammals, there are two closely related isoforms expressed from separate genes, namely GSK-3α and GSK-3β
). Both are ubiquitously expressed, although highest expression is found in the brain (1
). GSK-3 has been shown to phosphorylate more than 30 proteins involved in various cellular functions, including glycogen metabolism, signal transduction, apoptosis, gene transcription, microtubule dynamics, embryonic development, ubiquitin-mediated degradation, and nuclear/cytoplasmic trafficking, although only a handful of these proteins have been confirmed as physiological targets for GSK-3 (for reviews, see Refs. 2
). Most GSK-3 substrates require prior phosphorylation by another kinase at a serine or threonine located 4 residues C-terminal to the site phosphorylated by GSK-3 (i.e.
S/T(P), where X
is any amino acid) (2
). This downstream residue is termed a “priming” site and phosphorylation of the substrate by GSK-3 can be regulated indirectly by altering the activity of the “priming” kinase. Meanwhile, GSK-3 activity per se
is regulated directly by phosphorylation at two distinct sites, Ser21/9
). In addition, GSK-3 activity is regulated by interaction with inhibitory proteins. For example, activation of the Wnt signaling pathway results in the inhibition of GSK-3 activity, possibly by interaction with FRAT/GBP (6
In the brain, GSK-3 is expressed throughout the cell body and processes of post-mitotic neurons (7
). Its expression is widespread throughout all regions of the developing and adult brain, although it is highest in the hippocampus, thalamus, cortex, and Purkinje cells of the cerebellum in the adult, which are regions of greatest neuronal plasticity (7
). Elevated expression is also observed at the late embryonic/early post-natal period (7
). Overexpression of GSK-3β
activity in transgenic adult mice causes a relative reduction in the size of neuronal cell bodies (11
). Conversely, inhibition of GSK-3 in neuronal cell lines reduces axon elongation rates but increases the size of axon growth cones (13
). GSK-3 is also implicated in nerve growth factor control of axon growth (14
). These observations suggest that GSK-3 is an important regulator of neuronal process extension and synapse formation, although little is known about the mechanisms regulating the downstream effectors of GSK-3 in the brain.
Our data show that phosphorylation of specific residues on collapsin response mediator protein (CRMP) 2 by GSK-3 is a key part of the mechanism by which these molecules combine to induce axon growth and identifies GSK-3 as the modulator of an Alzheimer-related epitope.