Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway

Mol Cell. 2001 Apr;7(4):801-9. doi: 10.1016/s1097-2765(01)00224-6.

Abstract

To understand how the Wnt coreceptor LRP-5 is involved in transducing the canonical Wnt signals, we identified Axin as a protein that interacts with the intracellular domain of LRP-5. LRP-5, when expressed in fibroblast cells, showed no effect on the canonical Wnt signaling pathway by itself, but acted synergistically with Wnt. In contrast, LRP-5 mutants lacking the extracellular domain functioned as constitutively active forms that bind Axin and that induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin. Addition of Wnt caused the translocation of Axin to the membrane and enhanced the interaction between Axin and LRP-5. In addition, the LRP-5 sequences involved in interactions with Axin are required for LEF-1 activation. Thus, we conclude that the binding of Axin to LRP-5 is an important part of the Wnt signal transduction pathway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Axin Protein
  • COS Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Gene Expression / physiology
  • Glycogen Synthase Kinase 3
  • LDL-Receptor Related Proteins
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Mammals
  • Mice
  • Molecular Sequence Data
  • Mutagenesis / physiology
  • Protein Binding / physiology
  • Protein Structure, Tertiary
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Receptors, LDL / chemistry
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Repressor Proteins*
  • Signal Transduction / physiology*
  • Wnt Proteins
  • Zebrafish Proteins*

Substances

  • Axin Protein
  • LDL-Receptor Related Proteins
  • Low Density Lipoprotein Receptor-Related Protein-5
  • Lrp5 protein, mouse
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, LDL
  • Repressor Proteins
  • Wnt Proteins
  • Zebrafish Proteins
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3