Sci. STKE, 21 November 2006
Biochemistry Hsp90 Controls GSK-3 Kinase Specificity
L. Bryan Ray
Science, Sciences STKE, AAAS, Washington, DC 20005, USA
Glycogen synthase kinase 3 (GSK3) has long been known as a signaling component in insulin regulation of metabolism and, more recently, as a key part of the Wnt signaling pathway regulating cell proliferation, cell fate, and other processes during development. Unlike most other kinases, GSK3 is constitutively active and is regulated by inhibition. Full expression of this constitutive activity in the mammalian enzyme appears to require phosphorylation of a tyrosine residue in the activation loop of GSK3, which the enzyme accomplishes by intramolecular autophosphorylation, even though the kinase phosphorylates strictly serine and threonine residues on its exogenous substrates. Lochhead et al. explored the mechanism by which this switch in residue specificity is possible. Tagged GSK-3 synthesized in a rabbit reticulocyte lysate translation system showed rapid autophosphorylation that was inhibited by inhibitors of the molecular chaperone protein Hsp90. This chaperone-assisted tyrosine kinase activity was specific for tyrosine, as substitution of serine or threonine for the tyrosine in the activation loop reduced the extent of autophosphorylation. The tyrosine kinase activity was also insensitive to inhibitors or GSK-3s serine-threonine kinase activity toward its substrates. Attention is focused on the potential therapeutic value of inhibition of GSK-3 activity in a number of disease states, and the authors note that the auto-activation mechanism provides a possible target, with distinct specificity for inhibition from the serine-threonine kinase enzymatic activity of the mature enzyme.
P. A. Lochhead, R. Kinstrie, G. Sibbet, T. Rawjee, N. Morrice, V. Cleghon, A chaperone-dependent GSK3 transitional intermediate mediates activation-loop autophosphorylation. Mol. Cell 24, 627-633 (2006). [Online Journal]
Citation: L. B. Ray, Hsp90 Controls GSK-3 Kinase Specificity. Sci. STKE 2006, tw395 (2006).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882