A noncatalytic domain of glycogen synthase kinase-3 (GSK-3) is essential for activity

J Biol Chem. 2010 Mar 12;285(11):7957-63. doi: 10.1074/jbc.M109.091603. Epub 2010 Jan 15.


Glycogen synthase kinase-3 (GSK-3) isoforms, GSK-3alpha and GSK-3beta, are serine/threonine kinases involved in numerous cellular processes and diverse diseases, including Alzheimer disease, cancer, and diabetes. GSK-3 isoforms function redundantly in some settings, while, in others, they exhibit distinct activities. Despite intensive investigation into the physiological roles of GSK-3 isoforms, the basis for their differential activities remains unresolved. A more comprehensive understanding of the mechanistic basis for GSK-3 isoform-specific functions could lead to the development of isoform-specific inhibitors. Here, we describe a structure-function analysis of GSK-3alpha and GSK-3beta in mammalian cells. We deleted the noncatalytic N and C termini in both GSK-3 isoforms and generated point mutations of key regulatory residues. We examined the effect of these mutations on GSK-3 activity toward Tau, activity in Wnt signaling, interaction with Axin, and GSK-3alpha/beta Tyr(279/216) phosphorylation. We found that the N termini of both GSK-3 isoforms were dispensable, whereas progressive C-terminal deletions resulted in protein misfolding exhibited by deficient activity, impaired ability to interact with Axin, and a loss of Tyr(279/216) phosphorylation. Our data predict that small molecules targeting the divergent C terminus may lead to isoform-specific GSK-3 inhibition through destabilization of the GSK-3 structure.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Axin Protein
  • Cells, Cultured
  • Enzyme Activation / physiology
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3* / chemistry
  • Glycogen Synthase Kinase 3* / genetics
  • Glycogen Synthase Kinase 3* / metabolism
  • Humans
  • Isomerism
  • Kidney / cytology
  • Mutagenesis, Site-Directed
  • Phosphorylation
  • Proline / metabolism
  • Protein Structure, Tertiary
  • Repressor Proteins / metabolism
  • Signal Transduction / physiology*
  • Transfection
  • Tyrosine / metabolism
  • Wnt Proteins / metabolism
  • tau Proteins / metabolism


  • Axin Protein
  • MAPT protein, human
  • Repressor Proteins
  • Wnt Proteins
  • tau Proteins
  • Tyrosine
  • Proline
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha