| Here
in Dundee, Glycogen synthase kinase 3 is a very well known
kinase, which was initially linked to glycogen metabolism
by Prof Sir Philip Cohen almost 30 years ago. Since then,
of course, the kinase has been linked to many other functions
including WNT signalling and cell cycle control. GSK3 has
also been shown to phosphorylate several abundant proteins
in the brain, such as amyloid precurser protein, neurofilaments,
MAB 1B and Tau. It was therefore suggested that GSK3 may play
a role in the formation of diseases, which are characterised
by amyloid plaques, such as Alzheimers disease.
Kinasource
has collaborated with Calum Sutherland's group at the Division
for Pathology and Neuroscience, University of Dundee in order
to identify substrates of GSK3 in brain. We discovered that
isoforms of the 'collapsin response mediator protein' (CRMP),
also called 'dihydropyrimidinase-like' DRP are robust substrates
for GSK3. The proteins are phosphorylated at C-terminal sites.
Our findings show that this phosphorylation is probably important
for axon elongation of neurons. Importantly, the sites that
are phosphorylated by GSK3 were found to be biomarkers for
Alzheimers disease in a paper published 4 years ago Gu et
al., (2000) Neurofibrillary tangle-associated collapsin response
mediator protein-2 (CRMP-2) is highly phosphorylated on Thr-509,
Ser-518, and Ser-522. Biochemistry 39:4267-75. These findings
strengthen the hypothesis that GSK3 is involved in Alzheimers
disease. Interestingly, we found the GSK3 priming kinase is
probably DYRK, the mouse homologue of which is called mini
brain kinase. Without DYRK phosphorylating the priming site
Ser 522, GSK3 cannot phosphorylate CRMP. The gene for DYRK
is located on chromosome 21 (sic). We suggest that
DYRK may be a drug target for treating Alzheimers disease.
Adam
R. Cole, Axel Knebel, Nick A. Morrice, Laura S. Robertson,
Andrew J. Irving, Chris N. Connolly, and Calum Sutherland
J.
Biol. Chem. 2004 in press
GSK-3 phosphorylation of the Alzheimers epitope within collapsin
response mediator proteins regulates axon elongation in primary
neurons.
Division of Pathology and Neurosciences, University of Dundee,
Dundee, Tayside DD1 9SY, Kinasource Ltd, Laboratory 4.21,
MSI/WTB complex, Dow Street, DD1 5EH, Scotland.
Corresponding Author: c.d.sutherland@dundee.ac.uk
Elevated Glycogen Synthase Kinase-3 (GSK-3) activity is associated
with Alzheimers disease. We have found that Collapsin Response
Mediator Proteins (CRMP) 2 and 4 are physiological substrates
of GSK-3. The amino acids targeted by GSK-3 comprise a hyperphosphorylated
epitope first identified in plaques isolated from Alzheimers
brain. Expression of wild type CRMP2 in primary hippocampal
neurons or SH-SY5Y neuroblastoma cells promotes axon elongation.
However, a GSK-3-insensitive CRMP2 mutant has dramatically
reduced ability to promote axon elongation, a similar effect
to pharmacological inhibition of GSK-3. Hence, we propose
that phosphorylation of CRMP proteins by GSK-3 regulates axon
elongation. This work provides a direct connection between
hyperphosphorylation of these residues and elevated GSK-3
activity, both of which are observed in Alzheimer brain.
|
