A chaperone-dependent GSK3 beta transitional intermediate mediates activation-loop autophosphorylation

Lochhead, P.A., Kinstrie, R., Sibbet, G., Rawjee, T., Morrice, N. and Cleghon, V. (2006) A chaperone-dependent GSK3 beta transitional intermediate mediates activation-loop autophosphorylation. Molecular Cell, 24(4), pp. 627-633.

Abstract

Glycogen synthase kinase 3 (GSK3), a key component of the insulin and wnt signaling pathways, is unusual, as it is constitutively active and is inhibited in response to upstream signals. Kinase activity is thought to be increased by intramolecular phosphorylation of a tyrosine in the activation loop (Y216 in GSK3 beta), whose timing and mechanism is undefined. We show that GSK3 beta autophosphorylates Y216 as a chaperone-dependent transitional intermediate possessing intramolecular tyrosine kinase activity and displaying different sensitivity to small-molecule inhibitors compared to mature GSK3 beta. After autophosphorylation, mature GSK3 beta is then an intermolecular serine/threonine kinase no longer requiring a chaperone. This shows that autoactivating kinases have adopted different molecular mechanisms for autophosphorylation; and for kinases such as GSK3, inhibitors that affect only the transitional intermediate would be missed in conventional drug screens.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cleghon, Dr Vaughan and Kinstrie, Dr Ross and Lochhead, Ms Pamela and Morrice, Dr Nicholas and Sibbet, Dr Gary
• Authors: Lochhead, P.A., Kinstrie, R., Sibbet, G., Rawjee, T., Morrice, N., and Cleghon, V.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Cell