The low density lipoprotein receptor-related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity

J Biol Chem. 2006 Feb 24;281(8):4787-94. doi: 10.1074/jbc.M508657200. Epub 2005 Dec 19.


Glycogen synthase kinase 3 (GSK3) is a widely expressed Ser/Thr protein kinase that phosphorylates numerous substrates. This large number of substrates requires precise and specific regulation of GSK3 activity, which is achieved by a combination of phosphorylation, localization, and interactions with GSK3-binding proteins. Members of the Wnt canonical pathway have been shown to influence GSK3 activity. Through a yeast two-hybrid screen, we identified the Wnt canonical pathway co-receptor protein low density lipoprotein receptor-related protein 6 (LRP6) as a GSK3-binding protein. The interaction between the C terminus of LRP6 and GSK3 was also confirmed by in vitro GST pull-down assays and in situ coimmunoprecipitation assays. In vitro assays using immunoprecipitated proteins demonstrated that the C terminus of LRP6 significantly attenuated the activity of GSK3beta. In situ, LRP6 significantly decreased GSK3beta-mediated phosphorylation of tau at both primed and unprimed sites. Finally, it was also demonstrated that GSK3beta phosphorylates the PPP(S/T)P motifs in the C terminus of LRP6. This is the first identification of a direct interaction between LRP6 and GSK3, which results in an attenuation of GSK3 activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Binding Sites
  • CHO Cells
  • Cricetinae
  • Exons
  • Gene Expression Regulation, Enzymologic*
  • Glutathione Transferase / metabolism
  • Glycogen Synthase Kinase 3 / metabolism*
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • LDL-Receptor Related Proteins / metabolism
  • LDL-Receptor Related Proteins / physiology*
  • Leucine / chemistry
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Peptides / chemistry
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Recombinant Proteins / chemistry
  • Signal Transduction
  • Transfection
  • Two-Hybrid System Techniques
  • Wnt Proteins / metabolism
  • tau Proteins / chemistry


  • LDL-Receptor Related Proteins
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Peptides
  • Recombinant Proteins
  • Wnt Proteins
  • tau Proteins
  • Glutathione Transferase
  • Glycogen Synthase Kinase 3
  • Leucine