Angiopoietin-like 4 Is a Wnt Signaling Antagonist that Promotes LRP6 Turnover

Dev Cell. 2017 Oct 9;43(1):71-82.e6. doi: 10.1016/j.devcel.2017.09.011.

Abstract

Angiopoietin-like 4 (ANGPTL4) is a secreted signaling protein that is implicated in cardiovascular disease, metabolic disorder, and cancer. Outside of its role in lipid metabolism, ANGPTL4 signaling remains poorly understood. Here, we identify ANGPTL4 as a Wnt signaling antagonist that binds to syndecans and forms a ternary complex with the Wnt co-receptor Lipoprotein receptor-related protein 6 (LRP6). This protein complex is internalized via clathrin-mediated endocytosis and degraded in lysosomes, leading to attenuation of Wnt/β-catenin signaling. Angptl4 is expressed in the Spemann organizer of Xenopus embryos and acts as a Wnt antagonist to promote notochord formation and prevent muscle differentiation. This unexpected function of ANGPTL4 invites re-interpretation of its diverse physiological effects in light of Wnt signaling and may open therapeutic avenues for human disease.

Keywords: LRP6; Wnt/β-catenin signaling; angiopoietin-like 4; syndecan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-like 4 Protein
  • Angiopoietins / genetics
  • Angiopoietins / metabolism*
  • Animals
  • Endocytosis / physiology*
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism*
  • Phosphorylation
  • Receptors, LDL / metabolism*
  • Signal Transduction / physiology
  • Wnt Signaling Pathway / physiology*
  • Wnt3A Protein / metabolism
  • Xenopus
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism*
  • beta Catenin / metabolism*

Substances

  • ANGPTL4 protein, Xenopus
  • ANGPTL4 protein, human
  • Angiopoietin-like 4 Protein
  • Angiopoietins
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Receptors, LDL
  • Wnt3A Protein
  • Xenopus Proteins
  • beta Catenin