Front. Mol. Neurosci., 16 November 2011 | doi: 10.3389/fnmol.2011.00040

GSK-3: functional insights from cell biology and animal models

  • 1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
  • 2 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded in mammals by two genes that generate two related proteins: GSK-3α and GSK-3β. GSK-3 is active in cells under resting conditions and is primarily regulated through inhibition or diversion of its activity. While GSK-3 is one of the few protein kinases that can be inactivated by phosphorylation, the mechanisms of GSK-3 regulation are more varied and not fully understood. Precise control appears to be achieved by a combination of phosphorylation, localization, and sequestration by a number of GSK-3-binding proteins. GSK-3 lies downstream of several major signaling pathways including the phosphatidylinositol 3′ kinase pathway, the Wnt pathway, Hedgehog signaling and Notch. Specific pools of GSK-3, which differ in intracellular localization, binding partner affinity, and relative amount are differentially sensitized to several distinct signaling pathways and these sequestration mechanisms contribute to pathway insulation and signal specificity. Dysregulation of signaling pathways involving GSK-3 is associated with the pathogenesis of numerous neurological and psychiatric disorders and there are data suggesting GSK-3 isoform-selective roles in several of these. Here, we review the current knowledge of GSK-3 regulation and targets and discuss the various animal models that have been employed to dissect the functions of GSK-3 in brain development and function through the use of conventional or conditional knockout mice as well as transgenic mice. These studies have revealed fundamental roles for these protein kinases in memory, behavior, and neuronal fate determination and provide insights into possible therapeutic interventions.

Keywords: GSK-3, signal transduction, animal models, behavior

Citation: Kaidanovich-Beilin O and Woodgett JR (2011) GSK-3: functional insights from cell biology and animal models. Front. Mol. Neurosci. 4:40. doi: 10.3389/fnmol.2011.00040

Received: 30 August 2011; Accepted: 23 October 2011;
Published online: 16 November 2011.

Edited by:

Richard Scott Jope, University of Alabama at Birmingham, USA

Reviewed by:

Urs Albrecht, University of Fribourg, Switzerland
Hagit Eldar-Finkelman, Tel Aviv University, Israel

Copyright: © 2011 Kaidanovich-Beilin and Woodgett. This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.

*Correspondence: Oksana Kaidanovich-Beilin, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Room 983, Toronto, ON, Canada M5G 1X5. e-mail:; James Robert Woodgett, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Room 982, Toronto, ON, Canada M5G 1X5. e-mail:

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