GRB10 binds to LRP6, the Wnt co-receptor and inhibits canonical Wnt signaling pathway

Biochem Biophys Res Commun. 2007 May 11;356(3):648-54. doi: 10.1016/j.bbrc.2007.03.019. Epub 2007 Mar 12.


Low-density lipoprotein receptor-related protein 6 (LRP6) is a component of cell-surface receptors for Wnt proteins and Wnt is known to promote recruitment of Axin by LRP6 thereby inhibiting beta-catenin's degradation. We show here that growth factor receptor-bound protein10 (GRB10), a multi-modular adaptor protein that is known to associate with several transmembrane tyrosine kinase receptors, binds to the intracellular portion of LRP6 and negatively regulates Wnt signaling. GRB10 overexpression suppressed Wnt3a-, and LRP6-induced but not beta-catenin-induced TCF-dependent-reporter activities in HEK293T cells, suggesting that GRB10 functions upstream of beta-catenin. Actually, GRB10 overexpression attenuated the Wnt3a-induced accumulation of beta-catenin. In addition, RNAi-mediated down-regulation of endogenous GRB10 stimulated Wnt3a-induced reporter activities, indicating that GRB10 is indeed a novel negative regulator of the Wnt signaling pathway. The finding that GRB10 interferes with the binding of Axin to LRP6 indicated a possible molecular mechanism by which the overexpression of GRB10 suppresses Wnt signaling.

MeSH terms

  • Animals
  • Axin Protein
  • Binding Sites
  • GRB10 Adaptor Protein / metabolism*
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Mice
  • RNA Interference
  • Rats
  • Receptors, LDL / metabolism*
  • Repressor Proteins / antagonists & inhibitors
  • Signal Transduction / drug effects
  • Wnt Proteins / physiology*
  • beta Catenin / antagonists & inhibitors
  • src Homology Domains / physiology


  • Axin Protein
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Lrp6 protein, mouse
  • Receptors, LDL
  • Repressor Proteins
  • Wnt Proteins
  • beta Catenin
  • GRB10 Adaptor Protein