R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling

J Biol Chem. 2007 May 25;282(21):15903-11. doi: 10.1074/jbc.M701927200. Epub 2007 Mar 30.

Abstract

R-spondin proteins are newly identified secreted molecules that activate beta-catenin signaling. However, the mechanism of R-spondin action and its relationship with Wnt signaling remain unclear. Here we show that human R-spondin1 (hRspo1) is a high affinity ligand for the Wnt co-receptor LRP6 (K(d) = 1.2 nm). hRspo1 induces glycogen synthase kinase 3-dependent phosphorylation and activation of LRP6. DKK1, an LRP6 antagonist, inhibits hRspo1-induced LRP6 phosphorylation. We further demonstrate that hRspo1 synergizes with Frizzled5 in Xenopus axis induction assays and induces the phosphorylation of Dishevelled, a cytoplasmic component downstream of Frizzled function. Our study reveals interesting similarity and distinction between Wnt and R-spondin signaling.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Dishevelled Proteins
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • LDL-Receptor Related Proteins / agonists*
  • LDL-Receptor Related Proteins / antagonists & inhibitors
  • LDL-Receptor Related Proteins / metabolism*
  • Ligands
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational / physiology*
  • Signal Transduction / physiology*
  • Thrombospondins / metabolism*
  • Wnt Proteins / metabolism
  • Xenopus laevis
  • beta Catenin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • DKK1 protein, human
  • Dishevelled Proteins
  • Intercellular Signaling Peptides and Proteins
  • LDL-Receptor Related Proteins
  • LRP6 protein, human
  • Ligands
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Phosphoproteins
  • RSPO1 protein, human
  • Thrombospondins
  • Wnt Proteins
  • beta Catenin
  • Glycogen Synthase Kinase 3