IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis

Nature. 2008 Jul 17;454(7202):345-9. doi: 10.1038/nature07027. Epub 2008 Jun 4.

Abstract

Insulin-like growth-factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs). Although some of the actions of IGFBPs have been reported to be independent of IGFs, the precise mechanisms of IGF-independent actions of IGFBPs are largely unknown. Here we report a previously unknown function for IGFBP-4 as a cardiogenic growth factor. IGFBP-4 enhanced cardiomyocyte differentiation in vitro, and knockdown of Igfbp4 attenuated cardiomyogenesis both in vitro and in vivo. The cardiogenic effect of IGFBP-4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signalling. IGFBP-4 physically interacted with a Wnt receptor, Frizzled 8 (Frz8), and a Wnt co-receptor, low-density lipoprotein receptor-related protein 6 (LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Although IGF-independent, the cardiogenic effect of IGFBP-4 was attenuated by IGFs through IGFBP-4 sequestration. IGFBP-4 is therefore an inhibitor of the canonical Wnt signalling required for cardiogenesis and provides a molecular link between IGF signalling and Wnt signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Line, Tumor
  • Embryo, Nonmammalian / embryology
  • Heart / embryology*
  • Insulin-Like Growth Factor Binding Protein 4 / metabolism*
  • LDL-Receptor Related Proteins / metabolism
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Mice
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction*
  • Somatomedins / metabolism
  • Wnt Proteins / antagonists & inhibitors
  • Wnt Proteins / metabolism
  • Wnt3 Protein
  • Wnt3A Protein
  • Xenopus Proteins
  • Xenopus laevis
  • beta Catenin / metabolism

Substances

  • Insulin-Like Growth Factor Binding Protein 4
  • LDL-Receptor Related Proteins
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Lrp6 protein, mouse
  • Receptors, G-Protein-Coupled
  • Somatomedins
  • WNT3A protein, Xenopus
  • Wnt Proteins
  • Wnt3 Protein
  • Wnt3A Protein
  • Wnt3a protein, mouse
  • Xenopus Proteins
  • beta Catenin
  • frizzled 8 protein, mouse