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

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.
Mesh Terms:
Amino Acid Motifs, Animals, Binding Sites, CHO Cells, Cricetinae, Exons, Gene Expression Regulation, Enzymologic, Glutathione Transferase, Glycogen Synthase Kinase 3, Humans, Immunoblotting, Immunoprecipitation, LDL-Receptor Related Proteins, Leucine, Peptides, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Recombinant Proteins, Signal Transduction, Transfection, Two-Hybrid System Techniques, Wnt Proteins, tau Proteins
J. Biol. Chem.
Date: Feb. 24, 2006
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